Cancer  .  Next-Generation Tools  .  Protein Stability

Understanding lung cancer formation in molecular detail
Lung cancer is the leading cause of cancer-related death in the world, claiming 1.8 million lives in 2020. Although survival rates for most cancer types have improved significantly over the past 30 years, there has been little improvement in the 5-10 year survival rate for lung cancer patients. This demonstrates how important it is to learn more about the development of this disease and to investigate novel therapeutic approaches.

Lung tumours are classified into two main groups according to morphological features, localisation, marker expression and genetic properties: non-small cell lung cancer  (NSCLC) and small cell lung cancer (SCLC). In recent years the main focus of lung cancer-related research has been towards NSCLC, which accounts for roughly 80% of all diagnosed lung tumours. NSCLC is not homogeneous, and can be further classified based on morphological features and differences in marker expression into Adenocarcinomas (ADC) (50%), Squamous Cell Carcinomas (SCC) (40%) and Large Cell Carcinomas (10%). Most mouse model systems were developed to model ADC. Surprisingly, although 30% of all lung tumours diagnosed are SCC, so far autochthonous and inducible mouse models of this tumour type are scarce. Using publicly available genomic analyses of human NSCLC patient samples and comparing analyses of SCC and ADC tumours, we found that E3-ligases are frequently mutated in NSCLC together with mutations in p53 and the tumour drivers KRAS, EGFR and PIK3CA.

We utilize and combine novel techniques, like Crispr/Cas9 mediated genome editing for tumour onset and isogenic transplant models, to create human relevant surrogate models of complex diseases. We employ these models to study the early consequences of oncogenic transformation in the lung, and how cells in combination with expression of different tumour drivers. These new model will provide a foundation for understanding lung cancer formation in molecular detail.